Hirota, Yuki

写真a

Affiliation

School of Medicine, Department of Anatomy (Shinanomachi)

Position

Assistant Professor/Senior Assistant Professor

External Links
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Academic Degrees 【 Display / hide 】

  • 修士（医科学）, Osaka University, Coursework, 1999.03

  • 博士（医学）, Osaka University, Coursework, 2003.03

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Licenses and Qualifications 【 Display / hide 】

  • 死体解剖資格, 2020.03

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Research Areas 【 Display / hide 】

  • Life Science / Developmental biology

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Research Keywords 【 Display / hide 】

  • 大脳皮質発生

  • 神経細胞移動

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Research Themes 【 Display / hide 】

  • developmental biology of brain, 

    2007.01
    -
    Present

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Books 【 Display / hide 】

  • Tumors of the Central Nervous System. Volume 9.

    Hirota Yuki, Springer, 2012.01

    Scope: Proliferation of Neuroblasts in the Adult Brain: Role of Diversin

  • Neurogenesis in the adult brain I: Neurobiology.

    Hirota Yuki, Springer, 2011.01

    Scope: Neuronal migration in the adult brain.

  • Neural Development.

    Hirota Yuki, Springer-Verlag, 1999.01

    Scope: The regulatory mechanisms of neural development: roles of cell-aoutonomous and non-cell-autonomous cues in cell-fate decisions.

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Papers 【 Display / hide 】

  • Heterozygous Dab1 Null Mutation Disrupts Neocortical and Hippocampal Development

    Honda T., Hirota Y., Nakajima K.

    eNeuro 10 ( 4 )  2023.04

    　View Summary

    Loss-of-function mutations in Reelin and DAB1 signaling pathways disrupt proper neuronal positioning in the cerebral neocortex and hippocampus, but the underlying molecular mechanisms remain elusive. Here, we re-port that heterozygous yotari mice harboring a single autosomal recessive yotari mutation of Dab1 exhibited a thinner neocortical layer 1 than wild-type mice on postnatal day (P)7. However, a birth-dating study suggested that this reduction was not caused by failure of neuronal migration. In utero electroporation-mediated sparse labeling revealed that the superficial layer neurons of heterozygous yotari mice tended to elongate their apical dendrites within layer 2 than within layer 1. In addition, the CA1 pyramidal cell layer in the caudo-dorsal hippo-campus was abnormally split in heterozygous yotari mice, and a birth-dating study revealed that this splitting was caused mainly by migration failure of late-born pyramidal neurons. Adeno-associated virus (AAV)-medi-ated sparse labeling further showed that many pyramidal cells within the split cell had misoriented apical den-drites. These results suggest that regulation of neuronal migration and positioning by Reelin-DAB1 signaling pathways has unique dependencies on Dab1 gene dosage in different brain regions.

  • A Unique “Reversed” Migration of Neurons in the Developing Claustrum

    Oshima K., Yoshinaga S., Kitazawa A., Hirota Y., Nakajima K., Kubo K.I.

    Journal of Neuroscience 43 ( 5 ) 693 - 708 2023.02

    ISSN  02706474

    　View Summary

    The claustrum (CLA) is a cluster of neurons located between the insular cortex and striatum. Many studies have shown that the CLA plays an important role in higher brain function. Additionally, growing evidence suggests that CLA dysfunction is associated with neuropsychological symptoms. However, how the CLA is formed during development is not fully understood. In the present study, we analyzed the development of the CLA, especially focusing on the migration profiles of CLA neurons in mice of both sexes. First, we showed that CLA neurons were generated between embryonic day (E) 10.5 and E12.5, but mostly at E11.5. Next, we labeled CLA neurons born at E11.5 using the FlashTag technology and revealed that most neurons reached the brain surface by E13.5 but were distributed deep in the CLA 1 d later at E14.5. Time-lapse imaging of GFP-labeled cells revealed that some CLA neurons first migrated radially outward and then changed their direction inward after reaching the surface. Moreover, we demonstrated that Reelin signal is necessary for the appropriate distribution of CLA neurons. The switch from outward to “reversed” migration of developing CLA neurons is distinct from other migration modes, in which neurons typically migrate in a certain direction, which is simply outward or inward. Future elucidation of the characteristics and precise molecular mechanisms of CLA development may provide insights into the unique cognitive functions of the CLA.

  • Erratic and blood vessel-guided migration of astrocyte progenitors in the cerebral cortex

    Tabata H., Sasaki M., Agetsuma M., Sano H., Hirota Y., Miyajima M., Hayashi K., Honda T., Nishikawa M., Inaguma Y., Ito H., Takebayashi H., Ema M., Ikenaka K., Nabekura J., Nagata K.i., Nakajima K.

    Nature Communications 13 ( 1 )  2022.12

    　View Summary

    Astrocytes are one of the most abundant cell types in the mammalian brain. They play essential roles in synapse formation, maturation, and elimination. However, how astrocytes migrate into the gray matter to accomplish these processes is poorly understood. Here, we show that, by combinational analyses of in vitro and in vivo time-lapse observations and lineage traces, astrocyte progenitors move rapidly and irregularly within the developing cortex, which we call erratic migration. Astrocyte progenitors also adopt blood vessel-guided migration. These highly motile progenitors are generated in the restricted prenatal stages and differentiate into protoplasmic astrocytes in the gray matter, whereas postnatally generated progenitors do not move extensively and differentiate into fibrous astrocytes in the white matter. We found Cxcr4/7, and integrin β1 regulate the blood vessel-guided migration, and their functional blocking disrupts their positioning. This study provides insight into astrocyte development and may contribute to understanding the pathogenesis caused by their defects.

  • TPT1 Supports Proliferation of Neural Stem/Progenitor Cells and Brain Tumor Initiating Cells Regulated by Macrophage Migration Inhibitory Factor (MIF)

    Morimoto Y., Tokumitsu A., Sone T., Hirota Y., Tamura R., Sakamoto A., Nakajima K., Toda M., Kawakami Y., Okano H., Ohta S.

    Neurochemical Research 47 ( 9 ) 2741 - 2756 2022.09

    ISSN  03643190

    　View Summary

    One of the key areas in stem cell research is the identification of factors capable of promoting the expansion of Neural Stem Cell/Progenitor Cells (NSPCs) and understanding their molecular mechanisms for future use in clinical settings. We previously identified Macrophage Migration Inhibitory Factor (MIF) as a novel factor that can support the proliferation and/or survival of NSPCs based on in vitro functional cloning strategy and revealed that MIF can support the proliferation of human brain tumor-initiating cells (BTICs). However, the detailed downstream signaling for the functions has largely remained unknown. Thus, in the present study, we newly identified translationally-controlled tumor protein-1 (TPT1), which is expressed in the ventricular zone of mouse embryonic brain, as a downstream target of MIF signaling in mouse and human NSPCs and human BTICs. Using gene manipulation (over or downregulation of TPT1) techniques including CRISPR/Cas9-mediated heterozygous gene disruption showed that TPT1 contributed to the regulation of cell proliferation/survival in mouse NSPCs, human embryonic stem cell (hESC) derived-NSPCs, human-induced pluripotent stem cells (hiPSCs) derived-NSPCs and BTICs. Furthermore, gene silencing of TPT1 caused defects in neuronal differentiation in the NSPCs in vitro. We also identified the MIF–CHD7–TPT1–SMO signaling axis in regulating hESC–NSPCs and BTICs proliferation. Intriguingly, TPT1suppressed the miR-338 gene, which targets SMO in hESC–NSPCs and BTICs. Finally, mice with implanted BTICs infected with lentivirus-TPT1 shRNA showed a longer overall survival than control. These results also open up new avenues for the development of glioma therapies based on the TPT1 signaling pathway. Graphical Abstract: [Figure not available: see fulltext.]

  • Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice

    Ito N., Riyadh M.A., Ahmad S.A.I., Hattori S., Kanemura Y., Kiyonari H., Abe T., Furuta Y., Shinmyo Y., Kaneko N., Hirota Y., Lupo G., Hatakeyama J., Felemban Athary Abdulhaleem M., Anam M.B., Yamaguchi M., Takeo T., Takebayashi H., Takebayashi M., Oike Y., Nakagata N., Shimamura K., Holtzman M.J., Takahashi Y., Guillemot F., Miyakawa T., Sawamoto K., Ohta K.

    Science Translational Medicine 13 ( 587 )  2021.03

    ISSN  19466234

    　View Summary

    The lateral ventricle (LV) is flanked by the subventricular zone (SVZ), a neural stem cell (NSC) niche rich in extrinsic growth factors regulating NSC maintenance, proliferation, and neuronal differentiation. Dysregulation of the SVZ niche causes LV expansion, a condition known as hydrocephalus; however, the underlying pathological mechanisms are unclear. We show that deficiency of the proteoglycan Tsukushi (TSK) in ependymal cells at the LV surface and in the cerebrospinal fluid results in hydrocephalus with neurodevelopmental disorder-like symptoms in mice. These symptoms are accompanied by altered differentiation and survival of the NSC lineage, disrupted ependymal structure, and dysregulated Wnt signaling. Multiple TSK variants found in patients with hydrocephalus exhibit reduced physiological activity in mice in vivo and in vitro. Administration of wild-type TSK protein or Wnt antagonists, but not of hydrocephalus-related TSK variants, in the LV of TSK knockout mice prevented hydrocephalus and preserved SVZ neurogenesis. These observations suggest that TSK plays a crucial role as a niche molecule modulating the fate of SVZ NSCs and point to TSK as a candidate for the diagnosis and therapy of hydrocephalus.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

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Presentations 【 Display / hide 】

  • リーリンシグナルによるニューロン移動停止制御機構

    廣田ゆき, 仲嶋一範.

    第124回日本解剖学会総会全国学術集会, 

    2019.03
    , 

    Oral presentation (general)

  • リーリンシグナルによるニューロン移動停止制御機構

    廣田ゆき, 仲嶋一範.

    第41回日本分子生物学会年会 (横浜) , 

    2018.11
    , 

    Symposium, workshop panel (nominated)

  • 大脳皮質発生におけるリーリンシグナルの機能

    廣田ゆき, 仲嶋一範.

    2018年度生理学研究所研究会「神経発達・再生研究会」, 

    2018.10
    , 

    Oral presentation (invited, special)

  • How does Reelin signaling control the termination of neuronal migration?

    Yuki Hirota, Kazunori Nakajima

    第40回日本生物学的精神医学会・第61回日本神経化学会大会 (神戸) , 

    2018.09
    , 

    Oral presentation (general)

  • ApoER2 controls not only neuronal migration but also termination of migration in the developing cerebral cortex”

    Hirota Yuki

    22nd Biennial Meeting of the International Society for Developmental Neuroscience (Nara) , 

    2018.05
    , 

    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • How Multimodal ECM Regulates Cortical Layer Formation via Regulation of Neuronal Migration

    2024.04
    -
    2026.03

    学術変革領域研究(A), Principal investigator

  • 大脳皮質形成において神経細胞が移動を停止し配置する機構の解明

    2023.04
    -
    2027.03

    基盤研究(B), Principal investigator

  • ニューロン反発因子を介した大脳皮質形成機構

    2020.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • 大脳皮質層構造形成を司る糖蛋白質リーリンの受容体VLDLRを介した発生および病態時におけるニューロン移動制御機構

    2018
    -
    2019

    鈴木謙三記念医科学応用研究財団, 平成30年度調査研究助成, Other, Principal investigator

  • 受容体複合体による皮質ニューロン移動制御機構

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

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Awards 【 Display / hide 】

  • 公益信託成茂神経科学研究助成基金平成25年度研究助成

    2013.05, 公益信託成茂神経科学研究助成基金, マウス大脳皮質形成過程におけるリーリンシグナルの移動ニューロンへの作用機序

    Type of Award： Award from publisher, newspaper, foundation, etc.

  • 平成22年度名古屋市立大学医学会賞

    2010.12, 名古屋市立大学医学会, 非筋細胞ミオシンⅡによるマウス上衣細胞絨毛の平面極性制御

    Type of Award： Award from Japanese society, conference, symposium, etc.

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Courses Taught 【 Display / hide 】

  • HUMAN ANATOMY AND PHYSIOLOGY

    2024

  • EMBRYOLOGY

    2024

  • ANATOMY AND EMBRYOLOGY 2

    2024

  • ANATOMY

    2024

  • EMBRYOLOGY

    2023

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Courses Previously Taught 【 Display / hide 】

  • 発生学

    Keio University

    2018.04
    -
    2019.03
    , 

    Within own ｆaculty

  • 神経解剖学

    Keio University

    2018.04
    -
    2019.03
    , 

    Within own ｆaculty

  • 肉眼解剖学

    Keio University

    2018.04
    -
    2019.03
    , 

    Lecture

  • 発生学

    慶應義塾大学医学部

    2018.04
    -
    2019.03

  • 神経解剖学

    慶應義塾大学医学部

    2018.04
    -
    2019.03

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Social Activities 【 Display / hide 】

  • 慶應義塾大学第40回四谷祭 研究室ツアー

    2017.11
    -
    Present

  • 慶應義塾大学医学部解剖学教室仲嶋研究室オープンラボ

    2017.08
    -
    Present

  • 日本学術振興会ひらめきときめきサイエンスプログラム「脳の中で生まれる神経細胞〜脳のできるしくみと医療への応用〜」（名古屋市立大学医学研究科再生医学分野）

    2010.08
    -
    Present

  • 慶應義塾大学医学部ブリヂストン神経発生・再生学寄附講座 市民公開講座「交通外傷と神経再生」.

    2006.03
    -
    Present
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Memberships in Academic Societies 【 Display / hide 】

  • 日本分子生物学会

    　

  • 日本神経化学会

    　

  • 日本神経科学会

    　

  • 日本解剖学会

    　
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Committee Experiences 【 Display / hide 】

  • 2017.07
    -
    2023.03

    出版・広報委員会, 日本神経化学会

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